Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.
This ongoing study was designed using coproduction methodology to incorporate input from patients, caregivers, psychiatrists, pharmacists, nurses and researchers. For all five study sites, a minimum of two engagement/set-up meetings were conducted and two specific patient focus groups were held to guide protocol development and app design. Although a PRagmatic Explanatory Continuum Indicator Summary 2 (PRECIS-2) assessment tool was not used during the design of the study, the authors feel that based on a retrospective PRECIS-2 analysis (refer to online supplementary material for this analysis), this study does meet the criteria for a pragmatic study. The exploratory data collected in this study, although limited to a small number of patients, will help provide a better understanding of the ease of use for patients, HCPs and caregivers to inform the development of future software or hardware iterations.
Strickland Protocol Free 12
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Registration for the entire February 10-12 symposium is free and open to the public. To view the conference website and register, go to: www.tuskegee.edu/historyresearchsymposium. Contact hrs@tuskegee.edu if you have any difficulties registering.
The aim of this study was to analyze primary flexor tendon repair results in zones I and II, comparing the rupture rate and clinical outcomes of the controlled active motion (CAM) protocol with the modified Kleinert/Duran (mKD) protocol.
Patients who underwent surgery with traumatic flexor tendon lacerations in zones I and II were divided in three groups according to the type of rehabilitation protocol and period of management: group 1 included patients who underwent CAM rehabilitation protocol with six-strand Lim and Tsai suture after May 2014. Group 2 and 3 included patients treated by six-strand Lim Tsai suture followed by a modified Kleinert/Duran (modK/D) protocol with additional place and hold exercises between 2003 and 2005 (group 2) and between 2011 and 2013 (group 3).
The gut feeling that lead to change in our rehabilitation protocol could be explained by the heterogenous bias. A precise outcome analysis of group 1 could underline that in patients with complex hand trauma, nerve reconstruction, oedema or early extension deficit, an even more intensive and individual rehabilitation has to be performed to achieve better TAM at 6 or 12 weeks. Our study explicitly demonstrated a significant better outcome in the modK/D group compared to CAM group. This monocenter study is limited by its retrospective nature and the low number of patients.
The functional results after flexor tendon repair in zones I and II remain a current topic of debate with regard to suture technique and the postoperative rehabilitation protocol. The dilemma of achieving a balance between reduction of scar formation without increasing risk of re-rupture is still unsolved. New developments in primary tendon repair in recent decades include stronger core tendon repair techniques, judicious and adequate venting of critical pulleys, followed by a combination of passive and active digital flexion and extension [1].
In an earlier publication, we demonstrated the benefit of a six-strand Lim Tsai suture followed by a modified Kleinert/Duran (modK/D) protocol with additional place and hold exercises over a two-strand suture technique combined with Kleinert/Duran rehabilitation alone [6].
For 7 years, the six-strand Lim/Tsai suture technique followed by the modK/D rehabilitation protocol was the standard treatment for flexor tendon repair in zone 1 and 2 in our clinic. After initial good results referring to rupture rate and range of motion (ROM) [6], an increase in the rate of secondary tendon rupture was noted in due course from 2011 to 2013. In this context, we questioned the use of another rehabilitation protocol to improve our results: the CAM rehabilitation protocol after flexor tendon repair was introduced by Small et al. [7] to improve postoperative range of motion by preventing restrictive adhesions.
The aim of this study was to clarify if the CAM protocol after primary flexor tendon repair in zones I and II lead to better outcomes compared to the modK/D protocol or if the gut feeling that lead to change in our surgical technique could be explained by heterogenous bias.
This clinical study was approved by our ethic committee (KEK: 2017-02095). Clinical and functional outcome from patients who underwent surgery with traumatic flexor tendon lacerations in zones I and II were assessed retrospectively. Inclusion criteria and exclusion criteria are reported in Table 1. Patients were divided in three groups according to the type of rehabilitation protocol and period of management: group 1 included patients who underwent CAM rehabilitation protocol after six-strand Lim and Tsai suture (Table 2). Group 2 and 3 included, respectively, patients treated by six-strand Lim Tsai suture followed by a modified Kleinert/Duran (modK/D) protocol with additional place and hold exercises between 2003 and 2005 [6] and between 2011 and 2013 (Table 2).
The aim of this study was to clarify if the CAM protocol in flexor tendon repair (zone I and II) lead to better outcomes compared to the modK/D protocol or if the gut feeling that lead to change in our surgical technique could be explained by the heterogenous bias. Rupture rate was 4.7% at 12 weeks in group 1 (3/63 flexor tendon repairs) compared to 2% (1/51 flexor tendon repairs) in group 2 and 8% in group 3 (7/86 flexor tendon repairs). The TAM in group 1 (113) was significantly worse than the TAM in group 2 (141) but with similar extension deficits in group 1 and 2. The assessment of range of motion by the original Strickland classification system resulted in 20% excellent and 15% good outcomes in the CAM group 1 compared with 42% and 36% in the modK/D group 2.
Despite reassuring results on rupture rate in the three groups of patients and precise analysis of the CAM protocol outcomes, these study present two limitations: first, it was not possible to make a statistical analysis in group 3 due to heterogeneous reasons. Moreover, it was a monocenter retrospective study limited by its number of patients.
The gut feeling that lead to change in our rehabilitation protocol could be explained by the heterogenous bias. A precise outcome analysis of group 1 could underline that in patients with complex hand trauma, nerve reconstruction, oedema or early extension deficit, an even more intensive and individual rehabilitation has to be performed to achieve better TAM at 6 or 12 weeks. Our study explicitly demonstrated a significant better outcomes in the modK/D group compared to CAM group. This monocenter study is limited by its retrospective nature and the low number of patients.
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The study (Clinicaltrials.gov identifier NCT02939300) was designed by the principal investigators and conducted in accordance with the provision of the Declaration of Helsinki and Good Clinical Practice guidelines. The Dana-Farber Harvard Cancer Center (DF/HCC) Institutional review board committee approved the protocol. Funding was provided by Bristol Myers Squibb and Massachusetts General Hospital. The full study protocol is available as Supplementary Note 1 in the Supplementary Information file.
The full study protocol is available as Supplementary Note 1 in the Supplementary Information file. Any requests for additional clinical data will be reviewed by the Dana-Farber/Harvard Cancer Center (DF/HCC) Institutional Review Board (IRB). Patient-related data not included in the paper were generated as part of a clinical trial and are subject to patient confidentiality. Any data and materials (e.g., tissue samples or imaging data) that can be shared will need approval from the DF/HCC IRB and a Material Transfer Agreement in place. All data shared will be de-identified. Any requests for clinical data should be addressed to the corresponding author Priscilla K. Brastianos (pbrastianos@mgh.harvard.edu).
P.K.B., R.J.S., and D.P.C. conceived the study. P.K.B. wrote the protocol with input from R.J.S., D.P.C., S.L.C., A.G.H., E.R.G., and K.O. E.Q.L., N.W., J.V.C., U.C., D.F., A.E., B.O., N.U.L., W.C., A.B., D.J., I.D.J., M.D.W., J.D., C.A.B., M.M., B.V.M., A.K., C.A.B., P.S.J., H.A.S., E.R.G., K.O., D.P.C., and R.J.S. supported the clinical trial, including recruitment and/or management of patients on trial. A.G.H. performed the statistical analysis. N.N., A.K., M.R.S., J.L.M., and C.A.B. helped collect data and samples. E.R.G. was the imaging chair of the study. P.K.B., M.R.S., D.P.C., and R.J.S. wrote the manuscript. All authors interpreted the data, reviewed the manuscript, and approved the final version. 2ff7e9595c
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